Phase III Trial in Acute Promyelocytic Leukemia Patients

• Arm I:

• Induction therapy: Patients receive oral tretinoin twice daily and arsenic trioxide IV over 2 hours on days 1-60. Patients achieving hematological complete remission go on to receive consolidation therapy.
• Consolidation therapy: Patients receive oral tretinoin twice daily on days 1-14. Treatment with tretinoin repeats every 4 weeks for up to 7 courses. Patients also receive arsenic trioxide IV over 2 hours on days 1-5 in weeks 1-4. Treatment with arsenic trioxide repeats every 8 weeks for up to 4 courses.
• Arm II:

• Induction therapy: Patients receive tretinoin as in arm I induction therapy and idarubicin IV over 20 minutes on days 2, 4, 6, and 8. Patients achieving hematological complete remission go on to receive consolidation therapy.
• Consolidation therapy: Patients receive oral tretinoin twice daily on days 1-45, idarubicin IV over 20 minutes on days 1-4 and day 31, and mitoxantrone hydrochloride IV over 30 minutes on days 16-20.

Marrow samples are collected after completion of consolidation therapy and analyzed by reverse transcriptase-PCR for molecular remission. Patients achieving molecular remission (PML-RARa negative) go on to receive maintenance therapy.

• Maintenance therapy: Patients receive oral mercaptopurine once daily and methotrexate intramuscularly once weekly for 3 months. Treatment with mercaptopurine and methotrexate repeats every 3 months for 7 courses. After completion of course 1 of mercaptopurine and methotrexate, patients receive oral tretinoin once daily on days 1-15*. Treatment with tretinoin repeats every 3 months for 6 courses.

NOTE: *Patients do not receive mercaptopurine and methotrexate during tretinoin administration.

After completion of study therapy, patients are followed periodically for 5 years.

As of 14th September 2010, all patients needed to evaluate the primary endpoint (162 patients) have been recruited but the trial accrual continued in order to assess one secondary outcome (QoL)."

Inclusion criteria

• Signed written informed consent according to IGH/EU/GCP and national local laws
• Newly diagnosed APL by cytomorphology, confirmed also by molecular analysis*.
• Age ≤18 < 71 years
• WHO performance status 0 -2 included
• WBC at diagnosis ≤ 10 x 109/L
• Serum total bilirubin ≤ 3.0 mg/dL (≤ 51µmol/L)
• Serum creatinine ≤ 3.0 mg/dL (≤ 260 µmol/L)

The confirmation of diagnosis at genetic level (microspeckled PML nuclear distribution by PGM3 monoclonal antibody and/or PML/RARa fusion by RT-PCR and/or demonstration of t(15;17) by karyotyping) will be mandatory for patient eligibility. However, in order to avoid delay in treatment initiation, patients can be randomised on the basis of morphologic diagnosis only and before the results of genetic tests are available.

Exclusion criteria

• Age < 18 and ≥ 71
• WBC at diagnosis > 10 x 109/L
• Other active malignancy at time of study entry
• Lack of diagnostic confirmation at genetic level
• Significant arrhythmias, EKG abnormalities (*see below) or neuropathy
• Other cardiac contraindications for intensive chemotherapy (L-VEF <50%)
• Uncontrolled, life-threatening infections
• Severe non-controlled pulmonary or cardiac disease
• Women who are either pregnant or breast feeding, or of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they meet one of the following definitions:

• Amenorrhea;
• post surgical bilateral oophorectomy with or without hysterectomy;
• using a highly effective method of birth control (defined as those which result in a failure rate less than 1% per year) when used consistently and correctly such as implants, injectables, oral contraceptives, IUDs, sexual abstinence or vasectomized partner.
• Concomitant severe psychiatric disorder
• HIV positivity

*EKG abnormalities:

• Congenital long QT syndrome;
• History or presence of significant ventricular or atrial tachyarrhythmia
• Clinically significant resting bradycardia (<50 beats per minute)
• QTc > 450 msec on screening EKG (using the QTcF formula detailed on page 18)
• Right bundle branch block plus left anterior hemiblock, bifascicular block
• Use of other investigational drugs at the time of enrolment or within 30 days before study entry